Molecular mechanism of arsenite therapy against adult T-cell leukemia

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HTLV-1 is a causative agent of adult T-cell leukemia (ATL). Combination therapy containing arsenite has been shown to be effective to ATL patients.In this study, we identified that USP10 as a binding partner of HTLV-1 Tax oncoprotein. We established USP10 knockout mice and its knockout cells. USP10 mutants in USP10-knockout cells indicated that USP10 inhibits arsenite-induced apoptosis by reducing ROS production by forming stress granules. USP10 interacted with G3BP1 and the interaction is critical for inhibition of apoptosis induced by arsenite. USP10 knockdown in T-cells augmented apoptosis induced by arsenite. Arsenite induced more apoptosis in ATL cells than HTLV-1-uninfected T-cell lines. Tax augmented arsenite-induced apoptosis in cells, and the augmentation needs the interaction with USP10. These results indicated that USP10 is a cellular protein controlling sensitivity of leukemia T-cells to arsenite therapy.